Phenyl Carbamate Compound and a Composition for Preventing or Treating a Nerve Gas-Induced Disease Comprising the Same

ABSTRACT

The present invention relates to a composition for preventing or treating a nerve gas-induced disease comprising a phenyl carbamate compound and a method for preventing or treating a nerve gas-induced disease therewith. The present invention ensures the enhancement of neuroprotection, such that it is promising for preventing or treating various diseases caused by exposure to nerve gas.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition for preventing or treating a nerve gas-induced disease comprising a phenyl carbamate compound and a method for preventing or treating a neurological disease therewith.

2. Description of the Related Art

Organophosphorus nerve agents are the principal chemical warfare agents known to produce brain injury. They block hydrolysis of the neurotransmitter acetylcholine by inhibiting the enzyme acetylcholinesterase, resulting in greatly increased postsynaptic acetylcholine levels. This causes a spectrum of effects, including miosis, excess secretions, nausea, vomiting, and muscle fasciculations. At moderate to high doses, nerve agents also cause seizures and associated convulsions. If left untreated, seizures rapidly progress to status epilepticus (SE) and cause irreversible seizure related brain damage (SRBD).

Although there is little neuropathological data from patients who have survived nerve agent attacks, abundant evidence is available from animal models, many of which involve persistent SE. The profound brain damage produced by nerve agents was first described by Petras29; Lemercier et al 130; and McLeod et al. Since then, numerous studies have greatly enhanced the understanding of neuropathology resulting from nerve agent intoxication.

Neuroprotection as a Treatment for Nerve Agent Survivors. Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Neuroprotective treatments often target oxidative stress and excitotoxicity. both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection.

Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.

SUMMARY OF THE INVENTION

The present inventor has made intensive studies to develop a novel agent with excellent neuroprotecting activity which may be applied to effective treatment for various nerve gas-induced diseases. As results, the present inventor has discovered that the phenyl carbamate derivatives represented by above formula 1 provide highly enhanced neuroprotecting activity.

Accordingly, it is an object of this invention to provide a composition for preventing or treating a nerve gas-induced disease.

It is another object of this invention to provide a method for preventing or treating a nerve gas-induced disease.

Other objects and advantages of the present invention will become apparent from the following detailed description together with the appended claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the measurement of benzodiazepine-resistant electrographic status epilepsy model of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (compound 1) in the test (Rats) by a graph summarizing the percent change in EEG power over time. Only animals that underwent pilocarpine-induced status epilepticus and had an acceptable EEG signal were included in the analysis. In addition, the vehicle group includes historical controls derived from other temporally adjacent trials. The data are the mean (solid line) and 95% confidence intervals (shaded) of model predictions for each of the treatments normalized to the power at the time of the injection of test compound/vehicle. Differences between the groups were assessed using the non-parametric Mann-Whitney U-teat. The dashed lines represent the time points at which a significant difference was found between the two groups (p<0.05).

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of this invention, there is provided a composition for preventing or treating a nerve gas-induced disease comprising a compound represented by the following formula 1 or pharmaceutically acceptable salt thereof as an active ingredient:

wherein R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, and halogen; R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl C₁-C₃ alkyl and bridged C₆-C₈ bicycloalkane) wherein one of R⁶ and R⁷ is hydrogen; and R⁸ is C₁-C₅ alkyl.

The present inventor has made intensive studies to develop a novel agent with excellent neuroprotecting activity which may be applied to effective treatment for various nerve gas-induced diseases. As results, the present inventors have discovered that the phenyl carbamate derivatives represented by above formula 1 provide highly enhanced efficacy in treating or preventing nerve gas-induced disease.

The term “nerve gas” as used herein, refers to an agent that causes neurological injury or disrupts the mechanism by which nerves transfer messages to organs. The disruption may be caused by, i.e., blocking acetylcholinesterase, an enzyme that normally destroys acetylcholine, a neurotransmitter.

As used herein, “nerve gas” is used interchangeably with “nerve agent”.

The term “nerve gas-induced disease” as used herein, refers to any pathological condition which is caused by biological effects directly or indirectly derived from the exposure to nerve gas.

The term “alkyl” as used herein, refers to a straight or branched chain of saturated hydrocarbon group, e.g., methyl, ethyl, propyl, butyl, isobutyl, tert butyl and pentyl. “C₁-C₅ alkyl group” as used herein, refers to an alkyl group with carbon number of 1-5.

The term “aryl” as used herein, refers to a totally or partially unsaturated monocylic or polycyclic carbon rings having aromaticity. The aryl group of the present invention is preferably monoaryl or biaryl.

The term “bridged bicycloalkane” as used herein, refers to a cycloalkane containing two rings and two bridgehead carbon atoms shared by all three rings identifiable in the molecule.

According to a concrete embodiment, R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, chlorine, fluorine and iodine. More concretely, R¹, R², R³, R⁴ and R⁵ are not hydrogen at the same time.

According to a concrete embodiment, R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclohexyl, phenyl C₁-C₃ alkyl and bicycloheptane).

According to a concrete embodiment, R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclohexyl, benzyl and bicycle[2.2.1]heptane), and wherein one of R⁶ and R⁷ is hydrogen.

According to more concrete embodiment, the compound is selected from the group consisting of:

-   (1) 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate; -   (2) 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate; -   (3) 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; -   (4) 1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate; -   (5) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate; -   (6) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate; -   (7) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate; -   (8) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate; -   (9) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate; -   (10) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate; -   (11)     1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate; -   (12) 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate; -   (13) 1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate; -   (14) 1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate; -   (15) 1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamat; -   (16) 1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; -   (17) 1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; -   (18) 1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate; -   (19) 1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate; -   (20) 1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate; -   (21) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate; -   (22) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate; -   (23) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate; -   (24) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate; -   (25) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate; -   (26) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate; -   (27) 1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate; -   (28) 1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate; -   (29) 1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate; -   (30) 1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate; -   (31) 1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate; -   (32) 1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate; -   (33) 1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate; -   (34) 1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate; -   (35) 1-(2-fluorophenyl)-1-hydroxypropyl-2-carbamate; -   (36) 1-(2-iodophenyl)-1-hydroxypropyl-2-carbamate; -   (37) 1-(2-iodophenyl)-1-hydroxybutyl-2-carbamate; -   (38) 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate; and -   (39) 1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-carbamate.

According to even more concrete embodiment, the compound is selected from the group consisting of:

-   (1) 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate; -   (2) 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate; -   (3) 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; -   (5) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate; -   (8) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate; -   (12) 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate; -   (13) 1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate; -   (17) 1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate;     and -   (38) 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate.

According to concrete embodiment, the compound is in the form of racemate, enantiomer, diastereomer, a mixture of enantiomer or a mixture of diastereomer.

In this compound, 2 chiral carbons exist at positions 1 and 2 from phenyl group; thus, the compound may exist in the form of an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers, as well as a racemate.

According to more concrete embodiment, the racemate, enantiomer, diastereomer, mixture of enantiomer or mixture of diastereomer of the compound above described is selected from the group consisting of:

-   1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate, -   racemate of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate     and 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(S)-2-carbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-carbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate, -   racemate of 1-(2-chlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate     and 1-(2-chlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate, -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate and     1-(2-chlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-methylcarbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-propylcarbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxpropyl-(R)-2-N-isopropylcarbamate,     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate, -   1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-methylcarbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-propylcarbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate, -   1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate, -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-methylcarbamate and     1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-methylcarbamate -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-propylcarbamate and     1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-propylcarbamate, -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-isopropylcarbamate     and     1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate, -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-cyclopropylcarbamate     and     1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate, -   racemate of     1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-cyclohexylcarbamate     and     1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclohexylcarbamate, -   1-(2-fluorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate, -   1-(2-fluorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate, -   1-(2-iodophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate, -   1-(2-iodophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate, and -   1-(2-iodophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate.

As seen in the Examples, the present inventors have synthesized the compounds of various stereochemistries, and investigated their neuroprotecting activity by multilateral experiments.

The term “enantiomer” as used herein, refers to one of two stereoisomers that are mirror images of each other which are non-superposable due to existence of one or more chiral carbons. According to a concrete embodiment, the enantiomer of the present invention is one in which chiral carbons of C1 and C2 are diverse in stereo-configuration.

The term “diastereomer” as used herein, refers to stereoisomers that are not enantiomers, which occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent chiral centers thus are not mirror images of each other.

The term “racemate” as used herein, refers to one that has equal amounts of two enantiomers of different stereo-configuration, and lack in optical activity.

It would be obvious to the skilled artisan from the Examples below that the compounds of this invention are not limited to those with specific stereochemistry.

According to concrete embodiment, the pharmaceutically acceptable salt is produced by reacting the compound with an inorganic acid, an organic acid, an amino acid, sulfonic acid, an alkali metal or ammonium ion.

The pharmaceutically acceptable salts of the present invention are those which can be manufactured by using a method known in the art, for example, but not limited to, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphate, nitrate and carbonate; and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine; cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline; salts with sulfonic acid such as methane sulfonate, ethane sulfonate, benzene sulfonate and toluene sulfonate; metal salts by reaction with an alkali metal such as sodium and potassium; or salts with ammonium ion.

According to more concrete embodiment, the nerve gas-induced disease is selected from the group consisting of spasm, gastrointestinal distress, emesis, rhinorrhea, miosis, bronchoconstriction, fasciculation, floppy paralysis, apnea, diaphoresis and diarrhea.

In still another aspect of this invention, there is provided a method for preventing or treating a nerve gas-induced disease comprising administering a pharmaceutically effective amount of the composition of the present invention to a subject in need thereof.

As discussed, the compound of the present invention has a superior activity for neuroprotection. Therefore, it has potential to be developed as a therapeutic agent for preventing and treating various nerve gas-induced disease.

As the common descriptions regarding the compound of this invention and the diseases prevented or treated thereby are mentioned above, they are omitted herein to avoid excessive overlaps.

The composition of this invention may be provided as a pharmaceutical composition comprising a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt thereof.

The term “pharmaceutically effective amount” as used herein, refers to an amount enough to show and accomplish efficacies and activities for preventing, alleviating, treating a nerve gas-induced disease.

The pharmaceutical composition of this invention includes a pharmaceutically acceptable carrier besides the active ingredient compound. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention, which is commonly used in pharmaceutical formulations, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oils. The pharmaceutical composition according to the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition according to the present invention may be administered orally or parenterally, and concretely, administered parenterally. For parenteral administration, it may be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally or intra-articularly. More concretely, it is administered intramuscularly or intraperitoneally.

A suitable dosage amount of the pharmaceutical composition of the present invention may vary depending on pharmaceutical formulation methods, administration methods, the patient's age, body weight, sex, pathogenic state, diet, administration time, administration route, an excretion rate and sensitivity for a used pharmaceutical composition. Preferably, pharmaceutical composition of the present invention may be administered with a daily dosage of 0.001-10000 mg/kg (body weight).

According to the conventional techniques known to those skilled in the art, the pharmaceutical composition according to the present invention may be formulated with pharmaceutically acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dose form and a multi-dose form. Non-limiting examples of the formulations include, but not limited to, a solution, a suspension or an emulsion in oil or aqueous medium, an elixir, a powder, a granule, a tablet and a capsule, and may further comprise a dispersion agent or a stabilizer.

The present invention will now be described in further detail by examples. It would be obvious to those skilled in the art that these examples are intended to be more concretely illustrative and the scope of the present invention as set forth in the appended claims is not limited to or by the examples.

EXAMPLES Reaction Formula I Synthesis of Diol-1

A diol compound used in the synthesis of the carbamate compound may be synthesized by dihydroxylation of a trans-olefin compound. A diol compound having optical activity may be synthesized using a sharpless asymmetric dihydroxylation catalyst.

Reaction Formula II Synthesis of Diol-2

As indicated in the Reaction Formula II, the optically active substance of diol may also be synthesized using a reduction reagent after synthesizing a hydroxy-ketone compound using Haloro-Mandelic acid. In the Reaction Formula II, PG (protecting group) may be selected from the group consisting of trialkyl silyl group (e.g., a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silyl groups (wherein the total number of alkyl and aryl groups is three; e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), ester group [Ac (acetate), Bz (benzoate), Pv (pivaloate), Cbz (benzyl carbonate), BOC (t-butyl carbonate), Fmoc (9-fluoroenylmethyl)carbaonate, Alloc (allyl Carbonate), Troc (trichloroethyl carbonate), p-methoxybenzoate, methyl carbonate, and so on] and the like, wherein each alkyl group may be independently selected from the group consisting of linear, branched, or cyclic C₁-C₄ alkyl groups, and each aryl group may be independently selected from the group consisting of C₅-C₈ aryl groups, preferably a phenyl group.

Reaction Formula III Carbamation Reaction-1

A highly selectivity form of regioisomer of single carbamate of diol having halogen substituent at phenyl ring is prepared (Example 1˜14 and 36˜67 are synthesized by reaction formula III).

Reaction Formula IV Carbamation Reaction-2

Two substances in the form of regioisomers of a single carbamate of diol having halogen substituent at phenyl ring may be separated by flash column chromatography to obtain two kinds of single carbamate compounds. (Example 15˜35 and 68˜115 are synthesized by reaction formula IV)

Reaction Formula V Protection Reaction

In the Reaction Formula V, PG (protecting group) may be selected from the group consisting of trialkyl silyl group (e.g., a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silyl groups (wherein the total number of alkyl and aryl groups is three; e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), ester group[Ac(acetate), Bz (benzoate), Pv (pivaloate), Cbz (benzyl carbonate), BOC (t-butyl carbonate), Fmoc (9-fluoroenylmethyl)carbaonate, Alloc (allyl Carbonate), Troc(trichloroethyl carbonate), p-methoxybenzoate, methyl carbonate, and so on] and the like, wherein each alkyl group may be independently selected from the group consisting of linear, branched, or cyclic C₁-C₄ alkyl groups, and each aryl group may be independently selected from the group consisting of C₅-C₈ aryl groups, preferably a phenyl group.

In the Reaction Formula IV and V, A¹ is selected from the group consisting of hydrogen, C₁-C₅ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl C₁-C₃ alkyl and bridged C₆-C₈ bicycloalkane. Two substances in the form of regioisomers of a single carbamate of diol having halogen substituent at phenyl ring may be separated by flash column chromatography to obtain two kinds of single carbamate compounds.

Preparation Example 1 Synthesis of 1-(2-chlorophenyl)-trans-1-propene

48 ml of 2-chlorobenzenaldehyde (0.42 mol) and 49.7 ml of 3-pentanone (0.47 mol) were dissolved in 600 mL of hexane in flask, and then stirred with raising the temperature. 53.6 ml of Boron trifluoride etherate (BF₃OEt₂, 0.42 mol) was added to the resultant under reflux conditions. When the reaction was completed, water was added thereto. After layer separation, the obtained organic layer was washed twice with 1M sodium hydroxide solution (1M NaOH), and then the separated organic layer was washed with water. The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄) and concentrated. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (38 g, yield 58%).

¹H NMR (400 MHz, CDCl₃) δ 1.94 (d, J=4.8 Hz, 3H), 6.24 (m, 1H), 6.78 (d, J=14 Hz, 1H), 7.11˜7.51 (m, 4H)

Preparation Example 2 Synthesis of 1-(2-chlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 1 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (2.9 g, yield 83%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=7.6 Hz, 3H), 2.29˜2.33 (m, 2H), 6.28 (dt, 1=16 Hz, 6.4 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 7.13˜7.54 (m, 4H)

Preparation Example 3 Synthesis of 1-(2-chlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (8.0 g, yield 50˜90%).

¹H NMR (400 MHz, CDCl₃) δ 61.14 (d, J=6.8 Hz, 6H), 2.25˜2.57 (m, 1H), 6.20 (dd, J=16 Hz, 7.2 Hz, 1H), 7.64 (d, J=16 Hz, 1H), 7.12˜7.54 (m, 4H)

Preparation Example 4 Synthesis of 1-(2-chlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 1 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (10 g, yield 85%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=7.2 Hz, 3H), 1.33˜1.56 (m, 4H), 2.26˜2.32 (m, 4H), 6.24 (dt, J=15.6 Hz, 7 Hz, 1H), 6.78 (d, J=16 Hz, 1H), 7.13˜7.54 (m, 4H)

Preparation Example 5 Synthesis of 1-(2,4-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,4-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (2.4 g, yield 57%).

¹H NMR (400 MHz, CDCl₃) δ 1.95 (dd, J=6.8 Hz, 1.6 Hz, 3H), 6.24 (m, 1H), 6.72 (d, J=15.6 Hz, 1H), 7.18˜7.44 (m, 3H)

Preparation Example 6 Synthesis of 1-(2,4-dichlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 5 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (2.1 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=7.6 Hz, 3H), 2.20˜2.33 (m, 2H), 6.26 (dt, J=16 Hz, 6.8 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 7.18˜7.46 (m, 3H)

Preparation Example 7 Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 5 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (0.23 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.8 Hz, 6H), 2.53˜2.58 (m, 1H), 6.19 (dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31 (d, J=16.4 Hz, 1H), 7.18˜7.46 (m, 3H)

Preparation Example 8 Synthesis of 1-(2,4-dichlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 5 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (3.2 g, yield 40˜80%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, 0.1=7.2 Hz, 3H), 1.38˜1.52 (m, 4H), 2.25˜2.31 (m, 2H), 6.22 (dt, J=15.6 Hz, 6.8 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 7.18˜7.46 (m, 3H)

Preparation Example 9 Synthesis of 1-(2,6-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,6-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (0.4 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 1.98 (d, J=8 Hz, 3H), 6.23˜6.31 (m, 1H), 6.40 (d, J=16 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 10 Synthesis of 1-(2,6-dichlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 9 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (1.2 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 1.17 (t, J=7.6 Hz, 3H), 2.30˜2.37 (m, 2H), 6.29 (dt, J=16.4 Hz, 6 Hz, 1H), 6.37 (d, J=16.4 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 11 Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 9 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (0.23 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.8 Hz, 6H), 2.53˜2.58 (m, 1H), 6.19 (dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31 (d, J=16.4 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 12 Synthesis of 1-(2,6-dichlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 9 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (0.2 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 0.99 (t, J=7.2 Hz, 3H), 1.14˜4.59 (m, 4H), 2.30˜2.36 (m, 2H), 6.24 (dt, J=16 Hz, 6.6 Hz, 1H), 6.38 (d, J=16.4 Hz, 1H), 7.05˜7.33 (m, 3H)

Preparation Example 13 Synthesis of 1-(2,3-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,3-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (0.2 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ 1.94 (d, J=4.8 Hz, 3H), 6.24 (m, 1H), 6.78 (d, J=14 Hz, 1H), 7.11˜7.51 (m, 3H)

Preparation Example 14 Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (1.5 g, Preparation Example 1) was dissolved in 30 mL of the mixture of t-BuOH/H₂O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (13.7 g) and methane sulfone amide (CH₃SO₂NH₂, 0.76 g, 0.0080 mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na₂SO₃) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (1.65 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz 1H), 2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H), 7.22˜7.51 (m, 4H) ¹³C NMR (100 MHz, CDCl₃) δ 18.8, 71.5, 74.4, 127.1, 128.1, 128.9, 129.5, 132.6, 138.9

Preparation Example 15 Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (2.5 g, Preparation Example 1) was dissolved in 50 mL of the mixture of t-BuOH/H₂O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (23.5 g) and methane sulfone amide (CH₃SO₂NH₂, 1.27 g, 0.013 mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na₂SO₃) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (2.96 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz, 1H), 2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H), 7.22˜7.51 (m, 4H)

Preparation Example 16 Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol and 1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (6.53 g, Preparation Example 1) was dissolved in 45 mL of the mixture of acetone/t-BuOH/H₂O (5:1:1 V/V). At the room temperature, N-methylmorpholine-N-oxide (7.51 g) and OsO₄ (0.54 g) were added thereto and stirred for 2-3 hours. When the reaction was completed, the obtained product was washed with water and methylenechloride (MC). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (6.42 g, yield 80%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz, 1H), 2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H), 7.22˜7.51 (m, 4H)

Preparation Example 17 Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2-chlorophenyl)-trans-1-butene(Preparation Example 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.36 g, yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, 1-=7.4 Hz, 3H), 1.52˜4.65 (m, 2H), 2.01 (d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 18 Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2-chlorophenyl)-trans-1-butene (Preparation Example 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.84 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 2.01 (d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 19 Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-butanediol and 1-(2-chlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2-chlorophenyl)-trans-1-butene (Preparation Example 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (5.1 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 2.01 (d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 20 Synthesis of 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene(Preparation Example 3) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.96 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, 3=7.2 Hz, 6H), 1.83˜4.89 (m, 1H), 1.92 (d, J=5.6 Hz, 1H), 2.69 (d, J=6.4 Hz, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 21 Synthesis of 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene(Preparation Example 3) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (4.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7.2 Hz, 6H), 1.82˜1.90 (m, 1H), 1.93 (d, J=5.6 Hz, 1H), 2.79 (d, J=6 Hz, 1H), 3.53˜3.57 (m, 1H), 5.23˜5.25 (m, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 22 Synthesis of the mixture of 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene (Preparation Example 3) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7.2 Hz, 6H), 1.83˜1.90 (m, 1H), 1.92 (d, J=5.6 Hz, 1H), 2.69 (d, J=6.4 Hz, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 23 Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2-chlorophenyl)-trans-1-hexene (Preparation Example 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.37 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J=7.2 Hz, 3H), 1.35˜4.65 (m, 6H), 2.08 (d, J=4.4 Hz, 1H), 2.71 (d, J=5.2 Hz, 1H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H), 7.23˜7.53 (m, 4H)

Preparation Example 24 Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2-chlorophenyl)-trans-1-hexene (Preparation Example 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (4.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=6.6 Hz, 3H), 1.35˜1.65 (m, 6H), 2.08 (d, J=4.8 Hz, 1H), 2.70 (d, J=5.2 Hz, 1H), 3.80˜3.83 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.24˜7.56 (m, 4H)

Preparation Example 25 Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol and 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2-chlorophenyl)-trans-1-hexene (Preparation Example 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (7.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J=7.2 Hz, 3H), 1.26˜4.55 (m, 6H), 2.08 (d, J=4.4 Hz, 1H), 2.71 (d, J=5.6 Hz, 1H), 3.78˜3.84 (m, 1H), 5.04 (t, J=3.2 Hz, 1H), 7.24˜7.55 (m, 4H)

Preparation Example 26 Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene (Preparation Example 5) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.33 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H), 2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31 (dd, J=2.0 Hz, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H)

Preparation Example 27 Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene (Preparation Example 5) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.45 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H), 2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 28 Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene (Preparation Example 5) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.45 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 122 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H), 2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J==5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 29 Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.32 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07 (d, J=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 30 Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.43 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07 (d, J=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 31 Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.33 g, yield 60˜90%).

1H NMR (400 MHz, CDCl₃) δ 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07 (d, 1=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 77.31˜7.49 (m, 3H)

Preparation Example 32 Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.25 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 33 Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.36 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 34 Synthesis of the mixture of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.26 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 35 Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene (Preparation Example 8) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (1.1 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 36 Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene (Preparation Example 8) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (1.2 g, yield 60˜95%).

1H NMR (400 MHz, CDCl₃) δ 0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 37 Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene (Preparation Example 8) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.67 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 38 Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene (Preparation Example 9) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 39 Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene (Preparation Example 9) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.84 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, 3=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 40 Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene (Preparation Example 9) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.91 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, 0.7=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 41 Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (1.23 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64 (dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 42 Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.96 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64 (dd, J=0.8 Hz, J==4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 43 Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.86 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64 (dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 44 Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.25 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 45 Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.37 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 46 Synthesis of the mixture of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.47 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35 (d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 47 Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene (Preparation Example 12) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.36 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.8 Hz, 3H), 1.20˜4.31 (m, 4H), 1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33 (m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 48 Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene (Preparation Example 12) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.58 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.8 Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33 (m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 49 Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene (Preparation Example 12) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.62 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.8 Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33 (m, 1H), 5.25 (t, 1=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 50 Synthesis of methyl 2-(2-chlorophenyl)-(R)-2-hydroxyacetate

15 g of (R)-2-chloromandelic acid was mixed with methanol (CH₃OH, 150 ml) and phosphorus chloride oxide (POCl₃, 0.76 ml) in a flask by stirring using a magnetic stirrer at the room temperature for 6 hours. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na₂SO₃) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (15.64 g, yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 3.59 (d, J=5.2, 1H), 3.79 (t, J=6.0, 3H), 5.59 (d, J=5.2, 1H), 7.28˜7.43 (m, 4H)

Preparation Example 51 Synthesis of 2-(2-chlorophenyl)-(R)-2-hydroxy-N-methoxy-N-methylacetamide

N,O-dimethylhydroxylamine hydrochloride (N,O-dimethylhydroxylamine.HCl, 15.2 g) was dissolved in dichloromethane (DCM, 150 ml), and cooled to 0° C. using an ice-bath. Then, 77.7 ml of 2.0M trimethylaluminium in hexane was slowly added thereto in drop-wise manner for 30 minutes. Thereafter, the ice-bath was removed, and the obtained product was stirred at the room temperature for 2 hours. Methyl-2-(2-chlorophenyl)-(R)-2-hydroxyacetate (15.64 g) dissolved in dichloromethane (DCM, 150 ml) was added in drop-wise manner thereto at the room temperature for 30 minutes, and subjected to reflux for 12 hours. When the reaction was completed, the obtained product was cooled to 0° C., and washed by a slow drop-wise addition of hydrochloric acid (HCl, 200 ml). The obtained organic layer was washed with distilled water and brine, dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (14.68 g, yield 82%).

¹H NMR (400 MHz, CDCl₃) δ 3.23 (s, 3H), 3.28 (s, 3H), 4.33 (d, J=6.0 Hz, 1H), 5.81 (d, J=5.6 Hz, 1H), 7.23˜7.42 (m, 4H)

Preparation Example 52 Synthesis of 2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyl dimethlysiloxy)-N-methylacetamide

2-(2-chlorophenyl)-(R)-2-hydroxy-N-methoxy-N-methylacetamide (0.81 g, 3.52 mmol) obtained in Preparation Example 51 was dissolved in dichloromethane (DCM), and cooled to 0° C. Imedazole (0.36 g, 5.28 mmol) was slowly added, and stirred. TBDMS-Cl (t-butyldimethylsily chloride, 0.79 g, 5.28 mmol) was slowly added. When the reaction was completed, the reaction mixture was quenched with H₂O. The organic layer was separated and collected. The aqueous layer was extracted with CH₂Cl₂ (300 mL), dried over MgSO₄. Concentration under vacuum provided a title compound (0.97 g, 80˜95%).

¹H NMR (400 MHz, CDCl₃) δ −0.03 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 2.97 (s, 3H), 3.02 (s, 3H), 5.83 (s, 1H), 7.25˜7.60 (m, 4H)

Preparation Example 53 Synthesis of 1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy) propane-2-on

2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyldimethylsiloxy)-N-methylacetamide (0.9 g) obtained in Preparation Example 52 was dissolved in tetrahydrofuran (THF), and cooled to 0° C. 3.0M methyl magnesium bromide (MeMgBr, 2.18 ml) solution in ether was added thereto in drop-wise manner for 30 minutes, and the obtained product was stirred at 0° C. When the reaction was completed, diethylether was added thereto. The obtained product was washed with 10%(w/v) potassium hydrogen sulfate (KHSO₄, 100 ml) and then, washed again with brine. The obtained organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.69 g, yield 85˜95%).

¹H NMR (400 MHz, CDCl₃) δ −0.3 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 2.18 (s, 3H), 5.50 (s, 1H), 7.27˜7.56 (m, 4H)

Preparation Example 54 Synthesis of 1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)propane-2-on (0.14 g) obtained in Preparation Example 53 was dissolved in ether, and cooled to −78° C. Zinc borohydride (Zn(BH₄)₂) was slowly added thereto and the obtained product was stirred. When the reaction was completed, the obtained product was washed by H₂O. The obtained organic layer was washed with H₂O, dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.04 g, yield 25˜33%, cis:trans=2:1).

¹H NMR (400 MHz, CDCl₃) (s, 3H), 0.11 (s, 3H), 0.93 (S, 9H), 1.07 (d, J=6.4 3H), 2.05 (d, J=6.4 1H), 4.01˜4.05 (m, 1H), 5.18 (d, J=4.0, 1H), 7.20˜7.56 (m, 4H)

Preparation Example 55 Synthesis of 1-(2-chlorophenyl)-(R,S)-1,2-propanediol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol (10.38 g) obtained in Preparation Example 54 was dissolved in methanol (CH₃OH, 100 ml), and then, cooled to 0° C. 8M hydrochloric acid (HCl, 56.2 ml) was slowly added in drop-wise manner to the obtained product, and then, the obtained product was warmed to the room temperature, and stirred for 15 hours. When the reaction was completed, the obtained product was cooled to 0° C. 5N sodium hydroxide (NaOH, 30 ml) was slowly added thereto, and the obtained product was subjected to vacuum concentration. The obtained product was diluted with ethylacetate. The obtained organic layer was washed with distilled water, dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (7.05 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.07 (d, 3H), 2.01 (d, 1H), 2.61 (s, 1H), 4.21˜4.27 (m, 1H), 5.24 (d, 1H), 7.22˜7.64 (m, 4H)

Preparation Example 56 Synthesis of 1-(2-chlorophenyl)-(S,R)-1,2-propanediol

The substantially same method as described in Preparation Example 50˜55 was conducted, except that (S)-2-chloromandelic acid was used instead of (R)-2-chloromandelic acid, to obtain the title compound (5.04 g, yield 84%).

¹H NMR (400 MHz, CDCl₃) δ 1.07 (d, J=6.8, 3H), 2.00 (d, J=5.6, 1H), 2.54 (d, J=3.6, 1H), 4.22˜4.26 (m, 1H), 5.25 (t, J=3.2, 1H), 7.22˜7.65 (m, 4H)

Preparation Example 57 Synthesis of 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene (Preparation Example 13) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜ (m, 3H)

Preparation Example 58 Synthesis of 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene (Preparation Example 13) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.84 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜ (m, 3H)

Preparation Example 59 Synthesis of the mixture of 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene (Preparation Example 13) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.91 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜ (m, 3H)

Preparation Example 60 Synthesis of 1-(2-fluorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2-fluorobenzenaldehyde was used instead of 2-chlorobenzenealdehyde, to obtain the title compound (6.67 g, yield 61%).

¹H NMR (400 MHz, CDCl₃) δ 1.94 (d, J=6.8 Hz, 3H), 6.30˜6.38 (m, 1H), 6.57 (d, J=16 Hz, 1H), 7.00˜7.41 (m, 4H)

Preparation Example 61 Synthesis of 1-(2-fluorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2-fluorophenyl)-trans-1-propene (Preparation Example 60) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (6.46 g, yield 78%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 2.43 (d, J=3.6 Hz, 1H), 2.69 (d, J=4.8 Hz, 1H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m, 4H)

Preparation Example 62 Synthesis of 1-(2-fluorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2-fluorophenyl)-trans-1-propene (Preparation Example 60) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (3.29 g, yield 79%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 2.43 (d, J=3.6 Hz, 1H), 2.69 (d, J=4.8 Hz, 1H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m, 4H)

Preparation Example 63 Synthesis of 2-iodobenzenealdehyde

In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO₂, 14.86 g, 170.92 mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6 g, yield 91%).

¹H NMR (400 MHz, CDCl₃) δ 7.30˜7.99 (m, 4H), 10.10 (s, 1H)

Preparation Example 64 Synthesis of 1-(2-iodophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2-iodobenzenealdehyde (Preparation Example 63) was used instead of 2-chlorobenzenealdehyde, to obtain the title compound (3.4 g, yield 65%).

¹H NMR (400 MHz, CDCl₃) δ 1.95 (dd, J=6.8 Hz, 1.6 Hz, 3H), 6.09˜6.18 (m, 1H), 6.60 (dd, J=15.66 Hz, 1.8 Hz, 1H), 6.89˜7.84 (m, 4H)

Preparation Example 65 Synthesis of 1-(2-iodophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 64 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (8.5 g, yield 75%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (t, J=7.6 Hz, 3H), 2.26˜2.34 (m, 2H), 6.17 (dt, J=15.6 Hz, 6.6 Hz 1H), 6.57 (d, 115.6 Hz, 1H), 6.89˜7.85 (m, 4H)

Preparation Example 66 Synthesis of 1-(2-iodophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2-iodophenyl)-trans-1-propene (Preparation Example 64) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (3.4 g, yield 88%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=6.4 Hz, 3H), 2.26 (br s, 1H), 2.74 (br s, 1H), 3.99 (t, J=6.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 7.01˜7.87 (m, 4H)

Preparation Example 67 Synthesis of 1-(2-iodorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted was conducted, except that 1-(2-iodophenyl)-trans-1-propene (Preparation Example 64) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (7.4 g, yield 84%).

¹H NMR (400 MHz, CDCl₃) δ 1.26 (d, J=6.4 Hz, 3H), 2.35 (br s, 1H), 2.85 (br d, J=4.0 Hz, 1H), 3.98 (t, J=6.2 Hz, 1H), 4.80 (dd, J=5.0, 4.4 Hz, 1H), 7.00˜7.87 (m, 4H)

Preparation Example 68 Synthesis of 1-(2-iodophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted was conducted, except that 1-(2-iodophenyl)-trans-1-butene (Preparation Example 65) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (9.5 g, yield 84%).

¹H NMR (400 MHz, CDCl₃) δ 1.04 (t, J=7.6 Hz, 3H), 1.60˜1.71 (m, 2H), 2.07 (br s, 1H), 2.74 (br s, 1H), 3.71˜3.76 (m, 1H), 4.87 (d, J=4.8 Hz, 1H), 7.01˜7.87 (m, 4H)

Preparation Example 69 Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane

To a stirred solution of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14, 67 g, 0.35 mol) in CH₂Cl₂ (670 ml) was added Et₃N (200 mL, 1.43 mol) and TMSCl (113.9 mL, 0.89 mol) at 0° C. under N₂. The reaction mixture was allowed to stir at 0° C. for 3 hr. The reaction mixture was quenched with H₂O (650 mL) at 0° C. The organic layer was separated and collected. The aqueous layer was extracted with CH₂Cl₂ (300 mL), dried over MgSO₄, Concentration under vacuum provided a crude product (104.18 g, 117.44%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6 Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.207˜7.165 (m, 1H), 7.321˜7.245 (m, 2H), 7.566˜7.543 (m, 1H)

Preparation Example 70 Preparation of 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (Preparation example 15) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (8.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6 Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 71 Preparation of 1-(2-chlorophenyl)--1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)propane-1,2-diol (Preparation example 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (5.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6 Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 72 Preparation of 1-(2-chlorophenyl)-(S,R)-1,2-(Bis-tri methylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,R)-1,2-propanediol (Preparation example 56) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6 Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 73 Preparation of 1-(2-chlorophenyl)-(R,S)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,S)-1,2-propanediol (Preparation example 55) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6 Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 74 Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-butanediol (Preparation example 17) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 75 Preparation of 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-butanediol (Preparation example 18) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 76 Preparation of 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-1,2-butanediol (Preparation example 19) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.0 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 77 Preparation of 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 20) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2 Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 78 Preparation of 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 21) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2 Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 79 Preparation of 1-(2-chlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-1,2-butanediol (Preparation example 22) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2 Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 80 Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 23) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2 Hz, 3H), 1.35˜4.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H), 7.23˜7.53 (m, 4H)

Preparation Example 81 Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 24) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2 Hz, 3H), 1.35˜1.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H), 7.23˜7.53 (m, 4H)

Preparation Example 82 Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-1,2-hexanediol (Preparation example 25) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2 Hz, 3H), 1.35˜1.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H), 7.23˜7.53 (m, 4H)

Preparation Example 83 Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 26) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4 Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, >=5.0 Hz, 1H), 7.31 (dd, J=2.0 Hz, >=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H)

Preparation Example 84 Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 38) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, >=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.13˜7.36 (m, 3H)

Preparation Example 85 Preparation of 1-(2,3-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 57) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.2 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 86 Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 29) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 87 Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 41) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 88 Preparation of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 32) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.30˜7.53 (m, 3H)

Preparation Example 89 Preparation of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 44) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 90 Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 90) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.6 (m, 2H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 91 Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 47) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7 Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 92 Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 27) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.2 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4 Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 93 Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 39) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 94 Preparation of 1-(2,3-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 58) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.9 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 95 Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 30) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 96 Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 42) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 97 Preparation of 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 33) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.30˜7.53 (m, 3H)

Preparation Example 98 Preparation of 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 45) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 99 Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 36) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 100 Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 48) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7 Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 101 Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-propanediol (Preparation example 28) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4 Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 102 Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-propanediol (Preparation example 40) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 103 Preparation of 1-(2,3-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-1,2-propanediol (Preparation example 59) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 104 Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-butanediol (Preparation example 31) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.9 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 105 Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-butanediol (Preparation example 43) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 106 Preparation of 1-(2,4-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-butanediol (Preparation example 34) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.30˜7.53 (m, 3H)

Preparation Example 107 Preparation of 1-(2,6-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-butanediol (Preparation example 46) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 108 Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-hexanediol (Preparation example 37) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m, 3H), 1.30˜4.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜4.62 (m, 2H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 109 Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-hexanediol (Preparation example 49) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7 Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜4.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 110 Preparation of 1-(2-fluoroophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-fluoroophenyl)-(S,S)-1,2-propanediol (Preparation example 61) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=6.4 Hz, 3H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m, 4H)

Preparation Example 111 Preparation of 1-(2-fluorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-fluoroophenyl)-(R,R)-1,2-propanediol (Preparation example 62) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.5 g, yield 90˜420%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=6.4 Hz, 3H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m, 4H)

Preparation Example 112 Preparation of 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-propanediol (Preparation example 66) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.27 (d, J=6.4 Hz, 3H), 3.99 (t, J=6.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 7.01˜7.87 (m, 4H)

Preparation Example 113 Preparation of 1-(2-iodophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(R,R)-1,2-propanediol (Preparation example 67) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.26 (d, J=6.4 Hz, 3H), 3.98 (t, J=6.2 Hz, 1H), 4.88 (d, J=4.4 Hz, 1H), 7.00˜7.87 (m, 4H)

Preparation Example 114 Preparation of 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-butanediol (Preparation example 68) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ −0.053 (s, 9H), 0.044 (s, 9H), 1.04 (t, J=7.6 Hz, 3H), 1.60˜1.71 (m, 2H), 3.71˜3.76 (m, 1H), 4.87 (d, J=4.8 Hz, 1H), 7.01˜7.87 (m, 4H)

Table 1: Example of Sulfamate Compound

*: Sodium Salt

Example 1 Preparation of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (1)

To a stirred solution of crude 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (preparation example 69, 104 g, 0.31 mol) in toluene (670 mL) was added by Chlorosulfonyl isocynate (62.5 mL, 0.71 mol) at 0° C. The reaction mixture was stirred for 2 hr. The reaction mixture was quenched with ice water and then was stirred by additional cold H₂O (500 mL) for 2 hr. After separation of organic layer, the aqueous was adjusted pH2˜3 with sat. NaHCO₃ (400 mL) and extracted with EtOAc (300 mL×3). The EtOAc layer was washed with sat. NaHCO₃ (500 mL) and H₂O (500 mL). The organic phase was treated with Charcol for 1.5 hr. The organic phase was filtered with Cellite, dreid over MgSO₄. Filterion and concentration under vacuum provided the title compound of white solid (yield 85%(71.1 g), ee=99.9% MP=83˜84, [α]D=+57.8 (c=0.25, MeOH))

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68 (br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H), 7.55 (dd, J=1.6, J=7.8, 1 H)

¹³C NMR (100 MHz, CDCl₃) δ 16.4, 73.1, 75.0, 127.0, 128.4, 129.1, 129.5, 132.7, 138.0, 156.6

Example 2 Preparation of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (2)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 70) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (5.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68 (br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H), 7.55 (dd, J=1.6, J=7.8, 1H)

Example 3 Preparation of 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate (3)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 71) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (3.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68 (br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H), 7.55 (dd, J=7.8, 1H)

Example 4 Preparation of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-carbamate (4)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(S,R)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 72) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethyl silanyloxy) propane (Preparation example 69) to obtain the title compound (2.4 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68 (br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H), 7.55 (dd, J=1.6, J=7.8, 1H)

Example 5 Preparation of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(S)-2-carbamate (5)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(R,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 73) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.3 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68 (br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H), 7.55 (dd, J=1.6, J=7.8, 1H)

Example 6 Preparation of 1-(2-chlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate (6)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation example 74) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=7.4 Hz, 3H), 1.57˜1.73 (m, 2H), 3.01 (d, J=5.6 Hz, 1H), 4.74 (br s, 2H), 4.95 (dt, J=7.2, 8.8 Hz, 1H), 5.23 (t, J=5.6 Hz, 1H), 7.22˜7.54 (m, 4H)

Example 7 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate (7)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 75) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.5 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J=7.4 Hz, 3H), 1.53˜1.73 (m, 2H), 2.92 (s, 1H), 4.78 (br s, 2H), 4.91˜4.96 (m, 1H), 5.22 (d, J=5.5 Hz, 1H), 7.20˜7.54 (m, 4H)

Example 8 Synthesis of 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate (8)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 76) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7 Hz, 3H), 1.58˜1.74 (m, 2H), 2.94 (d, H=6 Hz, 1H), 4.69 (br s, 2H), 4.94˜4.99 (m, 1H), 5.24 (t, J=6 Hz, 1H), 7.23˜7.56 (m, 4H)

Example 9 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate(9)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 77) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 2.06 (m, 1H), 2.75 (d, J=6.8 Hz, 1H), 4.58 (br s, 2H), 4.85˜4.88 (m, 1H), 5.34˜5.37 (m, 1H), 7.22˜7.33 (m, 2H), 7.35˜7.37 (m, 1H), 7.51˜7.53 (m, 1H)

Example 10 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate (10)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 78) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 2.06 (m, 1H), 2.73 (d, J=6.8 Hz, 1H), 4.57 (br s, 2H), 4.85˜4.88 (m, 1H), 5.34˜5.37 (m, 1H), 7.24˜7.30 (m, 2H), 7.35˜7.37 (m, 1H), 7.51˜7.53 (m, 1H)

Example 11 Synthesis of 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate (11)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 79) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 2.08 (m, 1H), 2.76 (d, J=6.0 Hz, 1H), 4.59 (br s, 2H), 4.87 (dd, J=7.2 Hz, 4.4 Hz, 1H), 5.36 (t, J=4.6, 1H), 7.23˜7.54 (m, 4H)

Example 12 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxyhexyl-(S)-2-carbamate (12)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 80) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.3 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7 Hz, 3H), 1.33˜1.42 (m, 4H), 1.53˜1.71 (m, 2H), 2.89 (d, J=5.6 Hz, 1H) 4.64 (br s, 2H), 5.04 (dt, J=5.0, 9.0 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 7.23˜7.55 (m, 4H)

Example 13 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate (13)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 81) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89 (dd, J=5 Hz, 3H), 1.28˜1.43 (m, 4H), 1.52˜1.58 (m, 1H), 1.65˜1.72 (m, 1H), 2.90 (d, J=6 Hz, 1H), 4.64 (br s, 2H), 5.01˜5.06 (m, 1H), 5.22 (t, J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 14 Synthesis of 1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate (14)

The substantially same method as described in Example 1 was conducted, except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 82) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.1 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.88 (dd, J=5 Hz, 3H), 1.31˜1.43 (m, 4H), 1.63˜1.70 (m, 1H), 1.52˜1.60 (m, 1H), 3.06 (d, J=6 Hz, 1H), 4.75 (br s, 2H), 5.00˜5.05 (m, 1H), 5.21 (t, J=6 Hz, 1H), 7.22˜7.55 (m, 4H)

Example 15 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-methylcarbamate (15)

1-(2-chlorophenyl)-(S,S)-1,2-propanediol (2.4 g) obtained in Preparation Example 14, tetrahydrofuran (THF, 12 ml), and carbonyldiimidazole (CDI, 3.12 g) were put into a flask and stirred at the room temperature. After approximately 3 hours, methylamine solution (CH₃NH₂, 4 ml (33% in EtOH)) was added thereto. When the reaction was completed, the obtained product was washed with 1M HCl solution and ethylacetate (EA). The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography, to obtain the title compound (1.6 g, yield 51%).

¹H NMR (400 MHz, CDCl₃) δ 1.03˜1.25 (m, 3H), 2.76 (s, 3H), 3.34 (s, 1H), 4.80 (br s 1H), 5.04 (t, J=12.5 Hz, 1H), 5.14 (s, 1H), 7.20˜7.53 (m, 4H)

Example 16 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-propylcarbamate (16)

The substantially same method as described in Example 15 was conducted, except that propylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (0.79 g, yield 25%).

¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J=6.8 Hz, 3H), 1.20 (d, J=5.96 Hz, 3H), 1.49 (dd, J=14.2 Hz, 2H), 3.11 (d, J=6.28 Hz, 2H), 3.34 (s, 1H), 4.84 (br s, 1H), 5.05 (t, J=5.88 Hz, 1H), 5.14 (s, 1H), 7.22˜7.53 (m, 4H)

Example 17 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate (17)

The substantially same method as described in Example 15 was conducted, except that isopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.5 g, yield 41%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (dd, J=6.5 Hz, 6H), 1.19 (d, J=6.4 Hz, 3H), 3.21 (s, 1H), 3.73˜3.82 (m, 1H), 4.59 (br s, 1H), 5.01˜5.07 (m, 1H), 5.14 (t, J=5.8 Hz, 1H), 7.20˜7.53 (m, 4H)

Example 18 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate (18)

The substantially same method as described in Example 15 was conducted, except that cyclopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (2.2 g, yield 43%).

¹H NMR (400 MHz, CDCl₃) δ 0.50˜0.56 (m, 2H), 0.74 (d, J=7.21 Hz, 2H), 1.25 (s, 3H), 2.56˜2.61 (m, 1H), 3.72 (s, 1H), 4.98 (br s, 1H), 5.05˜5.11 (m, 1H), 7.16 (s, 1H), 7.23˜7.54 (m, 4H)

Example 19 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate (19)

The substantially same method as described in Example 15 was conducted, except that cyclohexylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.1 g, yield 26%).

¹H NMR (400 MHz, CDCl₃) δ 1.06˜4.40 (m, 7H), 1.56˜1.61 (m, 2H), 1.69˜1.71 (m, 2H), 1.87˜1.94 (m, 2H), 3.19 (d, J=4.32 Hz, 1H), 3.45 (s, 1H), 4.64 (br s 1H), 5.02˜5.07 (m, 1H), 5.14 (t, J=6.08 Hz, 1H) 7.20˜7.53 (m, 4H)

Example 20 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-benzyl carbamate (20)

The substantially same method as described in Example 15 was conducted, except that benzylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.2 g, yield 18%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=10 Hz, 3H), 3.12 (d, J=5 Hz, 1H), 4.37 (d, J=6 Hz, 2H), 5.12˜5.19 (m, 3H), 7.15˜7.56 (m, 9H)

Example 21 Synthesis of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-bicyclo[2,2,1]heptanescarbamate (21)

The substantially same method as described in Example 15 was conducted, except that 2-aminonorbornane was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 32%).

¹H NMR (400 MHz, CDCl₃) δ 1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜1.71 (m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H), 3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m, 1H), 7.22˜7.55 (m, 4H)

Example 22 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-methylcarbamate (22)

The substantially same method as described in Example 15 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (Preparation example 15) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (3.36 g, yield 60%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (d, J=6.8 Hz, 3H), 2.80 (d, J=4.8 Hz, 3H), 3.20 (d, J=4.4 Hz, 1H), 4.75 (br s, 1H), 5.03˜5.09 (m, 1H), 5.14˜5.17 (m, 1H), 7.22˜7.55 (m, 4H)

Example 23 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-propylcarbamate (23)

The substantially same method as described in Example 22 was conducted, except that propylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (3.1 g, yield 53%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7.6 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 1.51 (m, 2H), 3.09˜3.14 (m, 2H), 3.28 (d, J=4.4 Hz, 1H), 4.82 (br s, 1H), 5.03˜5.09 (m, 1H), 5.14˜5.17 (m, 1H), 7.22˜7.55 (m. 4H)

Example 24 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate (24)

The substantially same method as described in Example 22 was conducted, except that isopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (0.16 g, yield 27%).

¹H NMR (400 MHz, CDCl₃) δ 0.88˜1.16 (m, 6H), 1.19˜1.26 (m, 3H), 3.34 (s, 1H), 3.71˜3.78 (m, 1H), 4.62 (br s, 1H), 5.03 (t, J=5.8 Hz, 1H), 5.13 (d, J=4.9 Hz, 1H), 7.20˜7.53 (m, 4H)

Example 25 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate (25)

The substantially same method as described in Example 22 was conducted, except that cyclopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (3.7 g, yield 60%).

¹H NMR (400 MHz, CDCl₃) δ 0.49˜0.54 (m, 2H), 0.74 (d, J=7.2 Hz, 2H), 1.22 (s, 3H), 2.55˜2.60 (m, 1H), 3.16 (s, 1H), 5.00 (s, 1H), 5.04˜5.11 (m, 1H), 5.16 (s, 1H), 7.23˜7.54 (m, 4H)

Example 26 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate (26)

The substantially same method as described in Example 22 was conducted, except that cyclohexylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.9 g, yield 28%).

¹H NMR (400 MHz, CDCl₃) δ 1.05˜1.38 (m, 8H), 1.58˜1.70 (m, 3H), 1.85˜4.95 (m, 2H), 3.39˜3.47 (m, 1H), 3.56 (s, 1H), 4.79 (br s, 1H), 5.01˜5.07 (m, 1H), 5.14 (t, J=5.2 Hz, 1H), 7.20˜7.54 (m, 4H)

Example 27 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-benzylcarbamate (27)

The substantially same method as described in Example 22 was conducted, except that benzylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (0.52 g, yield 19%).

¹H NMR (400 MHz, CDCl₃) δ 1.25 (d, J=6 Hz, 3H), 1.64 (s, 1H), 3.13 (d, J=4.4 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 5.12˜5.19 (m, 2H), 7.23˜7.55 (m, 9H)

Example 28 Synthesis of 1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-bicyclo[2,2,1]heptanecarbamate (28)

The substantially same method as described in Example 22 was conducted, except that 2-aminonorbornane was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 20˜50%).

¹H NMR (400 MHz, CDCl₃) δ 1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜1.71 (m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H), 3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m, 1H), 7.22˜7.55 (m, 4H)

Example 29 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate (29)

The substantially same method as described in Example 15 was conducted, except that 1-(2-chlorophenyl)-1,2-propanediol (Preparation example 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (2.6 g, yield 45%).

¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, J=6 Hz, 3H), 2.81 (d, J=5 Hz, 3H), 3.14 (d, J=4 Hz, 1H), 4.72 (br s, 1H), 5.07 (dd, J=6 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 30 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate (30)

The substantially same method as described in Example 29 was conducted, except that propylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.0 g, yield 17%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7 Hz, 3H), 1.21 (d, J=6 Hz, 3H), 1.53 (dd, J=7 Hz, 2H), 3.13 (dd, J=7 Hz, 2H), 3.28 (d, 1H), 4.82 (S, 1H), 5.06 (dd, J=7 Hz, 1H), 5.16 (t, J=5 Hz, 1H), 7.21˜7.56 (m, 4H)

Example 31 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate (31)

The substantially same method as described in Example 29 was conducted, except that isopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (0.54 g, yield 16%).

¹H NMR (400 MHz, CDCl₃) δ 1.16 (dd, J=6 Hz, 6H), 1.21 (d, J=6 Hz, 3H), 3.23 (d, J=6 Hz, 1H), 3.75˜3.84 (m, 1H), 4.61 (br s, 1H), 5.06 (t, J=6 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 32 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate (32)

The substantially same method as described in Example 29 was conducted, except that cyclopropylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.0 g, yield 17%).

¹H NMR (400 MHz, CDCl₃) δ 0.50 (t, J=6 Hz, 2H), 0.77 (t, J=3 Hz, 2H), 1.12 (d, J=7 Hz, 3H), 2.53˜2.59 (m, 1H), 3.22 (d, J=4 Hz, 1H), 5.08 (dd, J=6 Hz, 1H), 5.15 (S, 1H), 7.22˜7.55 (m, 4H)

Example 33 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-, N-cyclohexylcarbamate (33)

The substantially same method as described in Example 29 was conducted, except that cyclohexylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (2.2 g, yield 33%).

¹H NMR (400 MHz, CDCl₃) δ 1.07˜1.17 (m, 3H), 1.21 (d, J=6 Hz, 3H), 1.29˜1.42 (m, 3H), 1.72 (dd, J=6 Hz, 2H), 1.92 (dd, J=6 Hz, 2H), 3.26 (d, J=4 Hz, 1H), 3.46 (t, J=4 Hz, 1H), 4.68 (d, J=6 Hz, 1H), 5.07 (dd, J=6 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 7.22˜7.55 (m, 4H)

Example 34 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate (34)

The substantially same method as described in Example 29 was conducted, except that benzylamine was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.3 g, yield 19%).

¹H NMR (400 MHz, CDCl₃) δ 1.25 (d, J=6 Hz, 3H), 3.16 (d, J=4 Hz, 1H), 4.36 (d, J=6 Hz, 2H), 5.14 (dd, J=6 Hz, 3H), 7.23˜7.56 (m, 9H), yield: 19% (1.3 g)

Example 35 Synthesis of 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate (35)

The substantially same method as described in Example 29 was conducted, except that 2-aminonorbornane was used instead of methylamine solution (CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 20˜50%).

¹H NMR (400 MHz, CDCl₃) δ 1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜4.71 (m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H), 3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m, 1H), 7.22˜7.55 (m, 4H)

Example 36 Synthesis of 1-(2,4-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (36)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 83) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethyl silanyloxy) propane (Preparation example 69) to obtain the title compound (1.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H) 4.96 (br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 37 Synthesis of 1-(2,6-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (37)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 84) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.6 g, yield 60˜90%)

Example 38 Synthesis of 1-(2,3-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (38)

The substantially same method as described in Example 1 was conducted, except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 85) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.4 g, yield 60˜90%)

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 39 Synthesis of 1-(2,4-dichlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate (39)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 86) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.3 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98 (d, J=5.6 Hz, 1H) 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19 (t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 40 Synthesis of 1-(2,6-dichlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate (40)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 87) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H), 1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50 (m, 2H), 7.17˜7.34 (m, 3H)

Example 41 Synthesis of 1-(2,4-dichlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate (41)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 88) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.30˜7.50 (m, 3H)

Example 42 Synthesis of 1-(2,6-dichlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate (42)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 89) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.4 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.16˜7.33 (m, 3H)

Example 43 Synthesis of 1-(2,4-dichlorophenyl)-(S)-1-hydroxyhexyl-(S)-2-carbamate (43)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 90) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=3.6 Hz, 3H), 1.28˜4.42 (m, 4H), 1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (br s, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m 3H)

Example 44 Synthesis of 1-(2,6-dichlorophenyl)-(5)-1-hydroxyhexyl-(5)-2-carbamate (44)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 91) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.1 g, yield 60˜90%)

¹H NMR (400 MHz, CDCl₃) δ 0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H), 1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (br s, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 45 Synthesis of 1-(2,4-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (45)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 92) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.2 g, yield 60˜90%),

1H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H), 4.96 (br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 46 Synthesis of 1-(2,6-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (46)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 93) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%),

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 47 Synthesis of 1-(2,3-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (47)

The substantially same method as described in Example 1 was conducted, except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 94) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.0 g, yield 60˜90%)

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 48 Synthesis of 1-(2,4-dichlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate (48)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 95) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.3 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98 (d, J=5.6 Hz, 1H), 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19 (t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 49 Synthesis of 1-(2,6-dichlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate (49)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 96) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.5 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H), 1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50 (m, 2H), 7.17˜7.34 (m, 3H)

Example 50 Synthesis of 1-(2,4-dichlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate (50)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 97) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜4.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.30˜7.50 (m, 3H)

Example 51 Synthesis of 1-(2,6-dichlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate (51)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 98) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.16˜7.33 (m, 3H)

Example 52 Synthesis of 1-(2,4-dichlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate (52)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 99) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.5 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=3.6 Hz, 3H), 1.28˜1.42 (m, 4H), 1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (br s, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m, 3H)

Example 53 Synthesis of 1-(2,6-dichlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate (53)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 100) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.4 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H), 1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (br s, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 54 Synthesis of 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate (54)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 101) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H) 4.96 (br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 55 Synthesis of 1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate (55)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 102) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.4 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 56 Synthesis of 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate (56)

The substantially same method as described in Example 1 was conducted, except that 1-(2,3-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 103) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 57 Synthesis of 1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate (57)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 104) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98 (d, J=5.6 Hz, 1H) 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19 (t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 58 Synthesis of 1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamate (58)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 105) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.4 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H), 1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50 (m, 2H), 7.17˜7.34 (m, 3H)

Example 59 Synthesis of 1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate (59)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 106) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.30˜7.50 (m, 3H)

Example 60 Synthesis of 1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate (60)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 107) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜4.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m, 1H), 7.16˜7.33 (m, 3H)

Example 61 Synthesis of 1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate (61)

The substantially same method as described in Example 1 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 108) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=3.6 Hz, 3H), 1.28˜1.42 (m, 4H), 1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (br s, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m, 3H)

Example 62 Synthesis of 1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate (62)

The substantially same method as described in Example 1 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 109) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.5 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H), 1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (br s, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 63 Synthesis of 1-(2-fluorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (63)

The substantially same method as described in Example 1 was conducted, except that 1-(2-fluorophenyl)-(S,S)-1,2-(Bis-trimethylsilanylcory)propane (Preparation Example 110) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (d, J=5.2 Hz, 3H), 2.93 (d, J=4.4 Hz, 1H), 4.71 (br s, 2H), 4.99˜5.06 (m, H), 7.04˜7.48 (m, 4H)

Example 64 Synthesis of 1-(2-fluorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (64)

The substantially same method as described in Example 1 was conducted, except that 1-(2-fluorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 111) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.6 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (d, J=5.2 Hz, 3H), 2.93 (d, >=4.4 Hz, 1H), 4.71 (br s, 2H), 4.99˜5.06 (m, H), 7.04˜7.48 (m, 4H)

Example 65 Synthesis of 1-(2-iodophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (65)

The substantially same method as described in Example 1 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 112) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=6.4 Hz, 3H), 3.09 (br s, 1H), 4.83 (br s, 2H), 5.00˜5.10 (m, 2H), 7.00˜7.76 (m, 4H)

Example 66 Synthesis of 1-(2-iodophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate (66)

The substantially same method as described in Example 1 was conducted, except that 1-(2-iodophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 113) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (1.7 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=6.4 Hz, 3H), 2.95 (d, J=3.6 Hz, 1H), 4.73 (br s, 2H), 5.01˜5.11 (m, 2H), 7.01˜7.86 (m, 4H)

Example 67 Synthesis of 1-(2-iodophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate (67)

The substantially same method as described in Example 1 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 114) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane (Preparation example 69) to obtain the title compound (2.1 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=6.4 Hz, 3H), 3.09 (br s, 1H), 4.83 (br s, 2H), 5.00˜5.10 (m, 2H), 7.00˜7.76 (m, 4H)

Example 68 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate (68)

1-(2-chlorophenyl)-(S,S)-1,2-propanediol (2.33 g, Preparation example 14) obtained in Preparation Example 14, tetrahydrofuran (THF, 12 ml), and carbonyldiimidazole (CDI, 3.04 g) were put into a flask and stirred at the room temperature. After approximately 3 hours, ammonia solution (NH₄OH, 4 ml) was added thereto. When the reaction was completed, the obtained product was washed with 1M HCl solution and ethylacetate (EA). The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography, to obtain the title compound (0.28 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.8 Hz, 3H), 2.13 (d, J=4.4 Hz, 1H), 4.12˜4.16 (m, 1H), 4.85 (br s, 2H), 5.98 (d, J=5.6 Hz, 1H), 7.24˜7.43 (m, 4H)

Example 69 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate (69)

The substantially same method as described in Example 68 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (Preparation Example 15) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (0.77 g, yield 16%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4 Hz, 3H), 2.04 (d, J=4.8 Hz, 1H), 4.11˜4.18 (m, 1H), 4.74 (br s, 2H), 6.00 (d, J=5.6 Hz, 1H), 7.24˜7.43 (m, 4H)

Example 70 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate (70)

The substantially same method as described in Example 68 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (Preparation Example 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (0.16 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.4 Hz, 3H), 2.04 (d, J=4.8 Hz, 1H), 4.11˜4.18 (m, 1H), 4.74 (br s, 2H), 6.00 (d, J=5.6 Hz, 1H), 7.24˜7.43 (m, 4H)

Example 71 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-methylcarbamate (71)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 15, to obtain the title compound (0.70 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, J=6.4 Hz, 3H), 2.80 (d, J=4.8 Hz, 3H), 3.12 (s, 1H), 4.09˜4.16 (m, 1H), 4.86 (br s, 1H), 5.99 (d, J=6.0 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 72 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-methylcarbamate (72)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 22, to obtain the title compound (0.69 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, J=6.4 Hz, 3H), 2.80 (d, J=4.8 Hz, 3H), 3.12 (s, 1H), 4.09˜4.16 (m, 1H), 4.86 (br s, 1H), 5.99 (d, J=6.0 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 73 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate (73)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 29, to obtain the title compound (0.73 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6 Hz, 3H), 2.15 (d, J=4 Hz, 1H), 2.81 (d, J=5 Hz, 3H), 4.12 (dd, J=6 Hz, 1H), 4.83 (br s, 1H), 6.00 (d, J=6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 74 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-propylcarbamate (74)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 16, to obtain the title compound (0.15 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H), 1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H), 4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 75 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-propylcarbamate (75)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 23, to obtain the title compound (0.04 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H), 1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H), 4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 76 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate (76)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 30, to obtain the title compound (0.15 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H), 1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H), 4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 77 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-isopropylcarbamate (77)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 17, to obtain the title compound (0.42 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.10 (d, J=6.0 Hz, 3H), 1.15˜1.19 (m, 6H), 2.41 (s, 1H), 3.76˜4.08 (m, 1H), 4.34 (s, 1H), 4.83 (br s 1H), 5.95 (d, J=5.3 Hz, 1H), 7.19˜7.39 (m, 4H)

Example 78 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-isopropylcarbamate (78)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 24, to obtain the title compound (0.5 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6 Hz, 3H), 1.20 (dd, J=9.2 Hz, 6H), 2.23 (s, 1H), 3.77˜3.82 (m, 1H), 4.10 (s, 1H), 4.76 (br s, 1H), 5.98 (d, J=5.6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 79 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate (79)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 31, to obtain the title compound (0.09 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=6 Hz, 3H), 1.21 (dd, J=6 Hz, 6H), 2.16 (d, J=5 Hz, 1H), 3.81 (t, J=6 Hz, 1H), 4.11 (d, J=5 Hz, 1H), 4.73 (br s, 1H), 5.98 (d, 1=5 Hz, 1H), 7.24˜741 (m, 4H)

Example 80 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-cyclopropylcarbamate (80)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 18, to obtain the title compound (0.53 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.53˜0.60 (m, 2H), 0.74 (s, 2H), 1.21 (d, J=6.0 Hz, 3H), 2.19 (s, 1H), 2.59 (s, 1H), 4.11˜4.15 (m, 1H), 5.13 (br s, 1H), 5.99 (d, J=5.20 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 81 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-cyclopropylcarbamate (81)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 25, to obtain the title compound (0.58 g, yield 10%).

1H NMR (400 MHz, CDCl₃) δ 0.53˜0.60 (m, 2H), 0.74 (s, 2H), 1.21 (d, J=6.0 Hz, 3H), 2.19 (s, 1H), 2.59 (s, 1H), 4.11˜4.15 (m, 1H), 5.13 (br s, 1H), 5.99 (d, J=5.20 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 82 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate (82)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 32, to obtain the title compound (0.38 g, yield 14%).

¹H NMR (400 MHz, CDCl₃) δ 0.71 (s, 2H), 1.19 (d, J=6 Hz, 3H), 2.45 (S, 1H), 2.57 (S, 1H), 4.08˜4.12 (m, 1H), 5.26 (s, 1H), 5.97 (d, J=4 Hz, 1H), 7.22˜7.54 (m, 4H)

Example 83 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-cyclohexylcarbamate (83)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 19, to obtain the title compound (0.24 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.10˜1.39 (m, 7H), 1.61 (s, 3H), 1.71˜1.74 (m, 2H), 1.87 (d, J=11.2 Hz, 1H), 2.48 (d, J=10.8 Hz, 1H), 3.46 (t, J=4 Hz, 1H), 4.10˜4.11 (m, 1H), 4.80 (br s 1H), 5.97 (d, J=5.6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 84 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-cyclohexylcarbamate (84)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 26, to obtain the title compound (0.35 g, yield 10%).

¹H NMR (400 MHz, CDCl₃) δ 1.10˜1.39 (m, 7H), 1.61 (s, 3H), 1.71˜1.74 (m, 2H), 1.87 (d, J=11.2 Hz, 1H), 2.48 (d, J=10.8 Hz, 1H), 3.46 (t, J=4 Hz, 1H), 4.10˜4.11 (m, 1H), 4.80 (br s 1H), 5.97 (d, J=5.6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 85 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate (85)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 33, to obtain the title compound (0.26 g, yield 10%).

¹H NMR (400 MHz, CDCl₃) δ 1.12˜1.19 (m, 3H), 1.22 (d, J=6 Hz, 3H), 1.27˜1.37 (m, 1H), 1.71 (t, J=6 Hz, 2H), 1.86˜1.88 (m, 1H), 1.97˜2.00 (m, 1H), 2.18 (d, J=4 Hz, 1H), 3.47 (S, 1H), 4.12 (t, J=6 Hz, 1H), 4.78 (S, 1H), 5.97 (d, J=6 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 86 Synthesis of 1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-benzylcarbamate (86)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 20, to obtain the title compound (0.19 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H), 4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6 Hz, 1H), 7.27˜7.42 (m, 9H)

Example 87 Synthesis of 1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-benzylcarbamate (87)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 27, to obtain the title compound (0.07 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H), 4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6 Hz, 1H), 7.27˜7.42 (m, 9H)

Example 88 Synthesis of 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate (88)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 34, to obtain the title compound (0.21 g, yield 14%).

1H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H), 4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6 Hz, 1H), 7.27˜7.42 (m, 9H)

Example 89 Synthesis of 1-(2,4-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate (89)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 26) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.05 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 2H), 7.50 (dd, J=8.4 Hz, 2.0 Hz, 1H)

Example 90 Synthesis of 1-(2,6-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate (90)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 38) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.07 g, yield 24%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40 (m, 3H)

Example 91 Synthesis of 1-(2,3-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate (91)

The substantially same method as described in Example 68 was conducted, except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 57) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.08 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 92 Synthesis of 1-(2,4-dichlorophenyl)-(S)-2-hydroxybutyl-(S)-1-carbamate (92)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 29) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.07 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 93 Synthesis of 1-(2,6-dichlorophenyl)-(S)-2-hydroxybutyl-(S)-1-carbamate (93)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 41) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.11 g, yield 29%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H), 1.18˜4.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 94 Synthesis of 1-(2,4-dichlorophenyl)-(S)-2-hydroxy-3-methyl-butyl-(S)-1-carbamate (94)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 32) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 95 Synthesis of 1-(2,6-dichlorophenyl)-(S)-2-hydroxy-3-methyl-butyl-(S)-1-carbamate (95)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 44) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.03 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, >=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 96 Synthesis of 1-(2,4-dichlorophenyl)-(S)-2-hydroxyhexyl-(S)-1-carbamate (96)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 35) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.21 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H), 1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, 1=8.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 97 Synthesis of 1-(2,6-dichlorophenyl)-(S)-2-hydroxyhexyl-(S)-1-carbamate (97)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 47) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.06 g, yield 29%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.2 Hz, 3H), 1.18˜4.33 (m, 4H), 1.48˜4.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, 1=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

Example 98 Synthesis of 1-(2,4-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate (98)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 27) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.04 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br 5, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 99 Synthesis of 1-(2,6-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate (99)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 39) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.09 g, yield 10-′30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40 (m, 3H)

Example 100 Synthesis of 1-(2,3-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate (100)

The substantially same method as described in Example 68 was conducted, except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 58) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.25 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, 3=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18-′7.22 (m, 3H),

Example 101 Synthesis of 1-(2,4-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-1-carbamate (101)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 30) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.08 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜4.01 (m, 1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 102 Synthesis of 1-(2,6-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-1-carbamate (102)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 42) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.09 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 103 Synthesis of 1-(2,4-dichlorophenyl)-(R)-2-hydroxy-3-methyl-butyl-(R)-1-carbamate (103)

The substantially-same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-propanediol (Preparation example 33) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 104 Synthesis of 1-(2,6-dichlorophenyl)-(R)-2-hydroxy-3-methyl-butyl-(R)-1-carbamate (104)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-propanediol (Preparation example 45) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 105 Synthesis of 1-(2,4-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-1-carbamate (105)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 36) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.21 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, 0.1=7.2 Hz, 3H), 1.18˜1.33 (m, 4H), 1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.30-′7.50 (m, 3H)

Example 106 Synthesis of 1-(2,6-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-1-carbamate (106)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 48) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.12 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, 0.1=7.2 Hz, 3H), 1.18˜1.33 (m, 4H), 1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

Example 107 Synthesis of 1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate (107)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-propanediol (Preparation example 28) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.05 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 108 Synthesis of 1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate (108)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-propanediol (Preparation example 40) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.06 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H), 4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40 (m, 3H)

Example 109 Synthesis of 1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-carbamate (109)

The substantially same method as described in Example 68 was conducted, except that 1-(2,3-dichlorophenyl)-1,2-propanediol (Preparation example 59) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.02 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H), 4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22 (m, 3H),

Example 110 Synthesis of 1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate (110)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-butanediol (Preparation example 31) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.07 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 111 Synthesis of 1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate (111)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-butanediol (Preparation example 43) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.10 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J=7.4 Hz, 3H), 0.92˜4.01 (m, 1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 112 Synthesis of 1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate (112)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-propanediol (Preparation example 34) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.04 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 113 Synthesis of 1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate (113)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-propanediol (Preparation example 46) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14); to obtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H), 3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 114 Synthesis of 1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate (114)

The substantially same method as described in Example 68 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-hexanediol (Preparation example 37) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.21 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H), 1.48˜4.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 115 Synthesis of 1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate (115)

The substantially same method as described in Example 68 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-hexanediol (Preparation example 49) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), to obtain the title compound (0.12 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, 0.1=7.2 Hz, 3H), 1.18˜1.33 (m, 4H), 1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (br s, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

TABLE 1 Compounds 1 to 67 having the structure of Chemical Formula 1 where ‘R⁷’ is a carbamoyl derivative and ‘R⁶’ is H n 1^(st) 2^(nd) R⁷ = carbamoyl No. R¹-R⁵ (position) Chiral Chiral R⁸ derivative, A¹ = R⁶ = H 1 Cl 1(2-) S S Me H H 2 Cl 1(2-) R R Me H H 3 Cl 1(2-) Rac. Rac. Me H H 4 Cl 1(2-) S R Me H H 5 Cl 1(2-) R S Me H H 6 Cl 1(2-) S S Et H H 7 Cl 1(2-) R R Et H H 8 Cl 1(2-) Rac. Rac. Et H H 9 Cl 1(2-) S S Isopropyl H H 10 Cl 1(2-) R R Isopropyl H H 11 Cl 1(2-) Rac. Rac. Isopropyl H H 12 Cl 1(2-) S S butyl H H 13 Cl 1(2-) R R butyl H H 14 Cl 1(2-) Rac. Rac. butyl H H 15 Cl 1(2-) S S Me Me H 16 Cl 1(2-) S S Me Propyl H 17 Cl 1(2-) S S Me Isopropyl H 18 Cl 1(2-) S S Me Cyclopropyl H 19 Cl 1(2-) S S Me Cyclohexyl H 20 Cl 1(2-) S S Me Benzyl H 21 Cl 1(2-) S S Me Bicyclo[2.2.1]heptane H 22 Cl 1(2-) R R Me Me H 23 Cl 1(2-) R R Me Propyl H 24 Cl 1(2-) R R Me Isopropyl H 25 Cl 1(2-) R R Me Cyclopropyl H 26 Cl 1(2-) R R Me Cyclohexyl H 27 Cl 1(2-) R R Me Benzyl H 28 Cl 1(2-) R R Me Bicyclo[2.2.1]heptane H 29 Cl 1(2-) Rac. Rac. Me Me H 30 Cl 1(2-) Rac. Rac. Me Propyl H 31 Cl 1(2-) Rac. Rac. Me Isopropyl H 32 Cl 1(2-) Rac. Rac. Me Cyclopropyl H 33 Cl 1(2-) Rac. Rac. Me Cyclohexyl H 34 Cl 1(2-) Rac. Rac. Me Benzyl H 35 Cl 1(2-) Rac, Rac. Me Bicyclo[2.2.1]heptane H 36 Cl 2(2,4-) S S Me H H 37 Cl 2(2,6-) S S Me H H 38 Cl 2(2,3-) S S Me H H 39 Cl 2(2,4-) S S Et H H 40 Cl 2(2,6-) S S Et H H 41 Cl 2(2,4-) S S Isopropyl H H 42 Cl 2(2,6-) S S Isopropyl H H 43 Cl 2(2,4-) S S butyl H H 44 Cl 2(2,6-) S S butyl H H 45 Cl 2(2,4-) R R Me H H 46 Cl 2(2,6-) R R Me H H 47 Cl 2(2,3-) R R Me H H 48 Cl 2(2,4-) R R Et H H 49 Cl 2(2,6-) R R Et H H 50 Cl 2(2,4-) R R Isopropyl H H 51 Cl 2(2,6-) R R Isopropyl H H 52 Cl 2(2,4-) R R butyl H H 53 Cl 2(2,6-) R R butyl H H 54 Cl 2(2,4-) Rac, Rac, Me H H 55 Cl 2(2,6-) Rac, Rac. Me H H 56 Cl 2(2,3-) Rac, Rac. Me H H 57 Cl 2(2,4-) Rac, Rac. Et H H 58 Cl 2(2,6-) Rac, Rac. Et H H 59 Cl 2(2,4-) Rac, Rac. Isopropyl H H 60 Cl 2(2,6-) Rac, Rac. Isopropyl H H 61 Cl 2(2,4-) Rac, Rac. butyl H H 62 Cl 2(2,6-) Rac, Rac. butyl H H 63 F 1(2-) S S Me H H 64 F 1(2-) R R Me H H 65 I 1(2-) S S Me H H 66 I 1(2-) R R Me H H 67 I 1(2-) S S Et H H

TABLE 2 Compounds 68 to 115 having the structure of Chemical Formula 1 where ‘R⁷’ is H and ‘R⁶’ is carbamoyl derivative n 1^(st) 2^(nd) R⁶ = carbamoyl No. R¹-R⁵ (position) Chiral Chiral R⁸ R⁷ = H derivative, A¹ = 68 Cl 1(2-) S S Me H H 69 Cl 1(2-) R R Me H H 70 Cl 1(2-) Rac. Rac. Me H H 71 Cl 1(2-) S S Me H Me 72 Cl 1(2-) R R Me H Me 73 Cl 1(2-) Rac. Rac. Me H Me 74 Cl 1(2-) S S Me H Propyl 75 Cl 1(2-) R R Me H Propyl 76 Cl 1(2-) Rac. Rac. Me H Propyl 77 Cl 1(2-) S S Me H Isopropyl 78 Cl 1(2-) R R Me H Isopropyl 79 Cl 1(2-) Rac. Rac. Me H Isopropyl 80 Cl 1(2-) S S Me H Cyclopropyl 81 Cl 1(2-) R R Me H Cyclopropyl 82 Cl 1(2-) Rac. Rac. Me H Cyclopropyl 83 Cl 1(2-) S S Me H Cyclohexyl 84 Cl 1(2-) R R Me H Cyclohexyl 85 Cl 1(2-) Rac. Rac. Me H Cyclohexyl 86 Cl 1(2-) S S Me H Benzyl 87 Cl 1(2-) R R Me H Benzyl 88 Cl 1(2-) Rac. Rac. Me H Benzyl 89 Cl 2(2,4-) S S Me H H 90 Cl 2(2,6-) S S Me H H 91 Cl 2(2,3-) S S Me H H 92 Cl 2(2,4-) S S Et H H 93 Cl 2(2,6-) S S Et H H 94 Cl 2(2,4-) S S Isopropyl H H 95 Cl 2(2,6-) S S Isopropyl H H 96 Cl 2(2,4-) S S Butyl H H 97 Cl 2(2,6-) S S Butyl H H 98 Cl 2(2,4-) R R Me H H 99 Cl 2(2,6-) R R Me H H 100 Cl 2(2,3-) R R Me H H 101 Cl 2(2,4-) R R Et H H 102 Cl 2(2,6-) R R Et H H 103 Cl 2(2,4-) R R Isopropyl H H 104 Cl 2(2,6-) R R Isopropyl H H 105 Cl 2(2,4-) R R Butyl H H 106 Cl 2(2,6-) R R Butyl H H 107 Cl 2(2,4-) Rac. Rac. Me H H 108 Cl 2(2,6-) Rac. Rac. Me H H 109 Cl 2(2,3-) Rac. Rac. Me H H 110 Cl 2(2,4-) Rac. Rac. Et H H 111 Cl 2(2,6-) Rac. Rac. Et H H 112 Cl 2(2,4-) Rac. Rac. Isopropyl H H 113 Cl 2(2,6-) Rac. Rac. Isopropyl H H 114 Cl 2(2,4-) Rac. Rac. Butyl H H 115 Cl 2(2,6-) Rac. Rac. Butyl H H

DPPH

The free radical scavenging capacity of the extracts was determined using DPPH (Sigma, U.S.A). DPPH solution (0.2 mM) was prepared in 99.8% methanol. Compounds were mixed with methanol to prepare the stock solution (30% w/w). Freshly prepared DPPH solution was 1 ml taken in test tubes and test compounds were 1 ml added followed to every test tube so that the final volume 2 ml and after 20 min, the absorbance was read at 517 nm using a spectrophotometer (OPTIZEN, Korea). Control sample was prepared containing the same volume without test compounds. 99.8% methanol was served as blank. % radical scavenging activity (RSA) of the DPPH free radical was measured by using the following equation (Rohmam, A., Riyanto, S., Yuniarti, N., Saputra, W. R., Utami, R. and Mulatsih, W. 2010. Antioxidant activity, total phenolic, and total flavaonoid of extracts and fractions of red fruit (Pandanus conoideus Lam). International Food Research Journal 17: 97˜106):

Radical scavenging activity (RSA) %=RAbs_(control)−Ab_(sample))/Abs_(control)]×100

TABLE 3 Measurement results of anti-oxidative stress of compounds Com- % radical scavenging pound activity No. (Concentration; 30%) 1 12.59 3 19.44 6 6.32 12 6.56 13 6.93 14 13.60 15 7.10 25 7.33 29 7.55 31 51.97 32 10.99 37 7.77 40 7.98 42 8.30 44 28.70 63 7.48 65 5.29 67 5.69

Lithium-Pilocarpine Model for Prevention Study

Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) of body weight 200˜230 g were used for these studies and housed 4˜5 rats per a cage for 4˜5 days. On the day prior to status epilepsy (SE), rats received 127 mg/kg lithium chloride (Sigma, St. Louis, Mo., U.S.A.) intraperitoneally (i.p.). Approximately 18˜20 h following this treatment, the rats were given 43 mg/kg pilocarpine (Sigma) intraperitoneally. An i.p. injection of 2 mg/kg methyl-scopolamine (Sigma) was administered 30 min prior to pilocarpine to block the effects of the muscarinic agonist on peripheral cholinergic receptors. The test drug was administered intraperitoneally (i.p.) in a volume of 2 ul/g body weight. Pharmacological effects of all the test materials were evaluated to compare the test groups (n=6) with a control group (n=6). Control group was administrated vehicle, only. The peak time was determined by administration test material's random dose for 0.5, 1, 2, 4 hour. The time that the most protect was defined peak time and ED50 was determined by other dose administration at peak time. The animals were then transferred to observation cages and observed continuously for 90 min. The seizure activity was elicited in approximately 95% of control group. Protection was defined as a complete absence of seizure grade 4˜5 based on Racine scale (Racine, 1972) over the 90-min observation period. The effective dose of compound necessary to protect against seizures to 50% of controls (i.e. ED50) was determined by log probit analysis using SPSS software program (SPSS Inc.). The obtained results are shown in following Table 4.

TABLE 4 Measurement results of Lithium-pilocarpine model of compounds in the test Compound Therapeutic effect (Example) Prevention(rat, ip) No. ED50(mg/kg) Peak Time(h) 1 18.0 2   2 71.9 0.5 3 31.7 0.5 4 ^(a)60 (50%)  — 6 ^(a)60 (100%) — 8  ^(a)60 (83.3%) — 9  ^(a)60 (83.3%) — 25 ^(a)60 (100%) — 29 ^(a)60 (100%) — 30 ^(a)73.6 (50%)   — 32 ^(a)60 (100%) — 36 ^(a)73.6 (100%)  — 37 ^(a)35 (100%) — 38 ^(a)73.6 (100%)  — 42  ^(a)60 (83.3%) — 46  ^(a)60 (66.7%) — 63 49.3  0.25 65 15.3 2   67 28.2 0.5 ^(a)Injection amount (mg/kg), Protection % = the percentage of prevention activity compared to the vehicle only, respectively.

Lithium-Pilocarpine Induced Status Epilepticus (SE) Model

Pilocarpine-induced SE shares similarities to nerve-agent intoxication and poisoning with other organophosphates. In the pilocarpine model, the ensuing seizures and SE are reproducible and well-characterized, whereas the seizure activity in organophosphate models is less well-defined and more variable (Todorovic M S et. al., (2012) Characterization of status epilepticus induced by two organophosphates in rats. Epilepsy Res 101:268-276). Animal models based on organophosphate analogs also have a high mortality rate, necessitating the need for antidotal pretreatment, which can modulate responsiveness to anticonvulsant therapy (Shih T M et. al, (2007) Anticonvulsants for nerve agent-induced seizures: the influence of the therapeuticdose of atropine. J Pharmacol Exp Ther 320:154-161). Therefore, the pilocarpine model has several advantages as a screen or test system for identifying treatments for organophosphate-induced SE.

Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) of body weight 200-230 g were used for these studies and housed 4-5 rats per a cage for 4˜5 days. On the day prior to SE, rats received 127 mg/kg lithium chloride (Sigma, St. Louis, Mo., U.S.A.) intraperitoneally (i.p.). Approximately 18-20 h following this treatment, the rats were given 43 mg/kg pilocarpine (Sigma) intraperitoneally. An i.p. injection of 2 mg/kg methyl-scopolamine (Sigma) was administered 30 min prior to pilocarpine to block the effects of the muscarinic agonist on peripheral cholinergic receptors. The effects of the test compounds dissolved in 30% Poly Ethylene Glycol 400 (Acros Organics, Geel, Belgium) or 20% Tween80 were studied at various times or 30 min after the occurrence of the first motor seizure or SE onset. The drug was administered intraperitoneally in a volume of 2 ul/g body weight. Pharmacological effects was evaluated to compare the test groups with a control group (n=8). Control group was administrated vehicle, only. The obtained results are shown in Table 5 and FIG. 1. (Reference; Racine R.J. (1972). Modification of seizure activity by electrical stimulation: II Motor seizure. Electroenceph. Clin. Neurophysiol. 32: 281-294.)

TABLE 5 Measurement results of Lithium-pilocarpine induced status epilepticus (SE) model of compounds in the test Therapeutic effect (Intervention, rat/iv) Compound time = 0 min time = 30 min (Example) after the first motor seizure after the first motor seizure No. ED50(mg/kg)/Peak Time(h) ED50(mg/kg)/Peak Time(h) 1 22.6 96.86 2 ^(a)46 (50%)  — 3  ^(a)46 (83.3%) — 4 ^(a)46 (100%) — 5  ^(a)46 (66.7%) — 6 ^(a)46 (100%) — 8 ^(a)46 (50%)  — 9  ^(a)46 (66.7%) — 15 ^(a)46 (100%) — 16 ^(a)46 (100%) — 18  ^(a)46 (66.7%) — 23 ^(a)46 (100%) — 25 ^(a)46 (100%) — 30  ^(a)46 (83.3%) — 31 ^(a)46 (100%) — 32 ^(a)46 (100%) — 36  ^(a)46 (66.7%) — 37 ^(a)46 (100%) — 38 ^(a)46 (50%)  — 40 ^(a)46 (100%) — 42  ^(a)46 (66.7%) — 43  ^(a)46 (16.7%) — 44  ^(a)46 (83.3%) — 45  ^(a)46 (33.3%) — 46 ^(a)46 (50%)  — 63 ^(a)46 (50%)  — 65 ^(a)46 (100%) — 67 ^(a)46 (100%) — ^(a)Injection amount(mg/kg), Protection % = the percentage of Intervention activity compared to the vehicle only, respectively.

Anti-Excitation Activity

In the MES test (Ref., G. Villetti et al. Neuropharmacology 40(2001) 866˜878), an electrical stimulus (mice; 50 mA, 60 Hz, 0.2 sec and rats; 150 mA 60 Hz, 0.2 sec in the test animal) supplied by 11A Shocker (IITC Life Science Company) was delivered through corneal electrodes. All mice assigned to any electroshock at peak time were treated with each test compound sample which was dissolved in 30% PEG400 prepared by saline solvent applied to oral before the test. If the test animal stretching their hind limb in a straight line weren't observed in the MES test, the results indicate that the test sample had an anti-excitation activity. Three doses of the test sample were administered orally to over 18 mice (6 mice per dose) for evaluating the respective doses at which 50% of the animals are protected from seizure (ED50). The value of ED50 (median effective dose) is calculated by Litchfield and Wicoxon log-probit method which is a dose-response relationship. Then, the test results are shown in following Table 6. Experimental animal, male ICR mice and male SD rats, were purchased from OrientBio or Nara biotech, Korea, and housed 4-5 mice per a cage for 4-5 days. The range of mice body weight was used between 19 and 26 grams. The obtained results are shown in following Table 6.

Neurotoxicity

The measurement of neurotoxicity of the test compounds was conducted by the method of Dunham and Miya [Dunham, N. W. and Miya, T. S. 1957. A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Am. Pharm. Assoc. (Baltimore) 46: 208-209]. In the method, motor abilities of the test animals can be determined by observing whether the test animals can walk without falling from a rotator, thereby determining the value of neurotoxicity of each compound. Term “TD50” means the respective dose of the test compound at which 50% of the test animal exhibit neurotoxicity. They were pre-trained on the rotarod (Rotarod; Columbus instrument, rota-max, USA) at 6 rpm for 5 min 24 hr prior to the test. The peak time was determined by administration test material's random dose for 0.5, 1, 2, 4 hour. To evaluate the minimal neurotoxicity of the compound, the mice were placed on the Rotarod (rod circle; 3 Cm) at 6 rpm and the test animal fails to maintain walking once or more during 1 minute, it can be regarded that the test animal exhibits neurotoxicity. The ratio of TD50 to ED50 (TD50/ED50) is called as a protective index, and useful as a parameter for comparison of pharmaceutical efficacy and neurotoxicity. The obtained results are shown in following Table 6.

[Statistical Analysis]

The obtained results are shown as mean±sem. The difference between the groups was statistically analyzed by ANOVA, and then, further examined by Dunnett's test or Bonferroni test. If p is less than 0.05, it was determined that the difference between the groups had statistical significance.

TABLE 6 Measurement results of anti-excitation activity of compounds in the test animals (Mice) Com- pound MES test(po) TD50 PI(TD50/ED50 No. ED50(mg/kg) Peak Time(h) (mg/kg po) in MES) 1 13.0 2 218.1 16.8  2 51.0   0.25 372.0 7.3 3 31.4 2 378.3 12.0  4 82.4   0.5 — — 5 84.1   0.5 275.2 3.3 6 22.2 1 — — 8  100 ^(a)(100%) — — — 9 67.1   0.5 — — 12 100 ^(a)(75%) — — — 13 200 ^(a)(75%) — — — 14  200 ^(a)(100%) — — — 15 100 ^(a)(75%) — — — 16 200 ^(a)(25%) — — — 18  200 ^(a)(100%) — — — 23 200 ^(a)(25%) — — — 25 200 ^(a)(25%) — — — 29 200 ^(a)(75%) — — — 30 200 ^(a)(25%) — — — 31 200 ^(a)(25%) — — — 32  200 ^(a)(100%) — — — 36 82.8 — — — 37 25.8   0.25 131.6 5.1 38 91.4 2 — — 39 41.2 1 — — 40 46.9 — — — 42 35.2   0.5 — — 43 100 ^(a)(25%) — — — 44 100 ^(a)(75%) — — — 46 35.2 1 — — 63  50 ^(a)(100%) — — — 65  50 ^(a)(100%) — — — 67  100 ^(a)(100%) — — —

Having described a preferred embodiment of the present invention, it is to be understood that variants and modifications thereof falling within the spirit of the invention may become apparent to those skilled in this art, and the scope of this invention is to be determined by appended claims and their equivalents. 

What is claimed is:
 1. A composition for preventing or treating a nerve gas-induced disease comprising a compound represented by the following formula 1 or pharmaceutically acceptable salt thereof as an active ingredient:

wherein R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and halogen; R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl C₁-C₃ alkyl and bridged C₆-C₈ bicycloalkane) wherein one of R⁶ and R⁷ is hydrogen; and R⁸ is C₁-C₅ alkyl.
 2. The composition according to claim 1, wherein R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, chlorine, fluorine and iodine.
 3. The composition according to claim 1, wherein R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclohexyl, phenyl C₁-C₃ alkyl and bicycloheptane).
 4. The composition according to claim 3, wherein R⁶ and R⁷ are each independently hydrogen or

(A¹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclohexyl, benzyl and bicycle[2.2.1]heptane), and wherein one of R⁶ and R⁷ is hydrogen.
 5. The composition according to claim 1, wherein the compound is selected from the group consisting of: (1) 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate; (2) 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate; (3) 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; (4) 1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate; (5) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate; (6) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate; (7) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate; (8) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate; (9) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate; (10) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate; (11) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate; (12) 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate; (13) 1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate; (14) 1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate; (15) 1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamat; (16) 1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; (17) 1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; (18) 1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate; (19) 1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate; (20) 1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate; (21) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate; (22) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate; (23) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate; (24) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate; (25) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate; (26) 1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate; (27) 1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate; (28) 1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate; (29) 1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate; (30) 1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate; (31) 1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate; (32) 1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate; (33) 1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate; (34) 1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate; (35) 1-(2-fluorophenyl)-1-hydroxpropyl-2-carbamate; (36) 1-(2-iodophenyl)-1-hydroxpropyl-2-carbamate; (37) 1-(2-iodophenyl)-1-hydroxybutyl-2-carbamate; (38) 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate; and (39) 1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-carbamate.
 6. The composition according to claim 5, wherein the compound is selected from the group consisting of: (1) 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate; (2) 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate; (3) 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; (5) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate; (8) 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate; (12) 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate; (13) 1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate; (17) 1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate; and (38) 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate.
 7. The composition according to claim 1, wherein the compound is in the form of racemate, enantiomer, diastereomer, a mixture of enantiomer or a mixture of diastereomer.
 8. The composition according to claim 1, wherein the pharmaceutically acceptable salt is produced by reacting the compound with an inorganic acid, an organic acid, an amino acid, sulfonic acid, an alkali metal or ammonium ion.
 9. The composition according to claim 1, wherein the nerve gas-induced disease is selected from the group consisting of spasm, gastrointestinal distress, emesis, rhinorrhea, miosis, bronchoconstriction, fasciculation, floppy paralysis, apnea, diaphoresis and diarrhea.
 10. A method for preventing or treating a nerve gas-induced disease comprising administering a pharmaceutically effective amount of the composition according to claim 1 to a subject in need thereof.
 11. The method according to claim 10, wherein the nerve gas induced disease is selected from the group consisting of spasm, gastrointestinal distress, emesis, rhinorrhea, miosis, bronchoconstriction, fasciculation, floppy paralysis, apnea, diaphoresis and diarrhea. 